Novel Medical Treatment Modalities of Endometriosis
Endometrioziste Yeni Medikal Tedavi Yöntemleri
Gülsüm Uysal1, Fulya Çağlı1, Hüseyin Aksoy2, Ülkü Aksoy1, Bașak Cıngıllıoğlu1, Eda Karakılıç1, Gökhan Açmaz1
1Kayseri Education and Research Hospital, Department of Obstetrics and Gynecology, Kayseri, Turkey; 2Kayseri Military Hospital, Department of Obstetrics and Gynecology, Kayseri, Turkey
Uzm. Dr. Gülsüm Uysal, Kayseri Eğitim ve Araştırma Hastanesi, 38100 Kayseri, Türkiye, Tel. 0352 338 21 49 Email. gulsumaykut@yahoo.com Geliş Tarihi: 09.01.2015 • Kabul Tarihi: 15.04.2015 ABSTRACT
Endometriosisis a very common gynecological condition causing infertility and pelvic pain affecting 6%–10% of women at their re- productive ages. The prevalence is 20%–50% and 20%–70% in infertile women and women with chronic pelvic pain, respectively.
The treatment of endometriosisis is always challenging for health- care professionals and there is no curative treatment option for endometriosis.
The treatment options for endometriosis can be classifi ed as medi- cal, surgical or combinations of the two approaches. Different medical agents exist for treatment of endometriosis. The most commonly used of these medical agents are non-steroidal anti- infl ammatory drugs, analgesics, gestagens or their derivatives, combined oral contraceptive pills, and more recently the levonorg- estrel intrauterine system. Although there are numerous treatment options, available pharmacological treatment options in endo- metriosis are not fully satisfactory. Numerous new medical treat- ment agents are currently being tested in clinical trials in different phases. The purpose of the present review is to discuss the new medical treatment modalities in endometriosis.
Key words: endometriosis; medical treatment; pelvic pain
ÖZET
Endometriozis üreme çağındaki kadınların %6–10’unu etkileyen infertilite ve pelvik ağrıya neden olan yaygın görülen jinekolojik bir durumdur. İnfertil kadınların %20–50’sinde, kronik pelvik ağrısı olan kadınların ise %20–70’inde görülür. Endometriozis tedavisi her za- man klinik açıdan zor bir durum olmakla beraber tam șifa ile sonla- nan bir tedavi seçeneği yoktur.
Endometriosis tedavisi medikal ve cerrahi ya da her ikisinin beraber kullanımı șeklinde sınıflandırılabilir. Tedavide birçok farklı medikal ajanlar kullanılabilir. En sık kullanılan medikal ajanlar non-sterod antiinflamatuar ilaçlar, analjezikler, gestajen ve türevleri, kombine oral kontraseptifler ve son zamanlarda levonorgestrel içeren rahim içi araçlardır. Kullanımda olan birçok farmakolojik tedavi seçeneği olmasına rağmen, hiçbiri tam anlamıyla bașarı sağlamamaktadır.
Introduction
Endometriosis, defi ned as the presence of tissue that is morphologically and biologically similar to endome- trial glands and stroma in locations outside the uterus.
It is a common disease aff ecting up to 6-10% of women at their reproductive ages1-3.
Women with subfertility and pelvic pain have preva- lence rates ranging from 20% to 50% and from 20% to 70%, respectively1-3. Ectopic implants of endometriosis are primarily located in pelvic organs; ovaries, anterior and posterior cul de sacs, broad ligaments, uterosacral ligaments, uterus, and fallopian tubes. Endometriosis can be defi ned as an estrogen-dependent chronic in- fl ammatory disease that causes a broad spectrum of symptoms; however, the cardinal clinical features are infertility and pelvic pain3.
Th e definitive pathogenesis of endometriosis rema- ins unclear, but several theories explaining diff erent aspects and locations of disease have been proposed.
Retrograde menstruation and coelomic metapla- sia theories are the most widely accepted theories4. Although the exact pathogenesis of endometriosis is not completely elucidated, it is currently accepted that endometriosis is a complex and multifactorial condi- tion of uncertain etiology. Hormonal, immunological, infl ammatory, genetic, environmental, and possibly even lifestyle factors are implicated in the pathophysi- ology of the disease4-9.
Çeșitli yeni medikal tedavi ajanları klinik denemelerden geçmekte- dir. Bu derlemenin amacı endometriosis tedavisinde yeni medikal tedavi yöntemlerini tartıșmaktır.
Anahtar kelimeler: endometriyozis; medikal tedavi; pelvik ağrı
Th e management of women with endometriosis is al- ways challenging for healthcare professionals. Th ere is no absolute cure for endometriosis. Treatment may be medical or surgical. Th e goal of surgical treatment of endometriosis is to remove endometriotic implants and scar tissue. Surgical intervention can be either con- servative or defi nitive.
Medical treatment of endometriosis ranges from symp- tomatic control to treatments that aim to suppress the ovarian production of estrogen. Current medical treat- ment options include non-steroidal anti-infl ammatory drugs (NSAIDs) and analgesics for symptomatic pain control, application of gestagens or their derivatives and combined oral contraceptive pills (COCPs) to suppress ovulation, gonadotrophin-releasing hor- mone agonists (GnRH) or GnRH antagonists, and danazol for menopausal simulation. More recently the levonorgestrel intrauterine system with/without the combination of the previous treatment options are available10-13. However, the present pharmacologi- cal treatment options in endometriosis are not fully satisfactory. Numerous new medical treatment agents are currently being tested in clinical trials in diff erent phases. Th e purpose of the present review is to discuss the new medical treatment modalities used in the man- agement of endometriosis.
Current New Medical Agents in Endometriosis Treatment
Progesterone Receptor-Binding Molecules (PRBM) With a view to blocking or modifying downstream eff ects, progesterone receptor modulators interact with progesterone receptor. PRBM decrease not only progesterone but also estradiol. Progesterone antago- nist mifepristone (RU-486) and the selective pro- gesterone receptor modulators asoprisnil and CDB- 4124 (a 21-substituted-19-nor-progestin) have been proposed as therapeutic agents for endometriosis14,15. Mefi pristone is reported to have benefi ts in some patients in terms of reduced pain and regression of lesions16-18.
Selective Estrogen Receptor -agonist
Infl amation and macrophages are known to lead to the over expression of estrogen receptor-a (ER-a) and estrogen receptor-b (ER-b) in women with endome- triosis. Estrogen receptor-a agonists mediate most of the classic eff ects of estrogen. However, ER-b-selective
agonists possess anti-infl ammatory properties19. In a mouse model of endometriosis, ERB-041 induced complete regression of lesions in 40% to 75% of ani- mals from diff erent series, and recovered lesions ex- pressed ER-a, but not ER-b-mRNA20.
Selective Estrogen Receptor Modulators (SERMs) Development and progression of endometriosis should be interfered with the drugs blocking the estrogen recep- tors. Stratton et al. showed in humans that endometrio- sis related pelvic pain is likely to be treated by raloxifene, which means that, SERMs may act in the modulation of lesions and chronic pelvic pain like an estrogen21.
New Promising Groups of Drugs Tested in Animals and Humans
Tumor Necrosis Factor Alpha (TNF-) Blockers
Th e infl ammatory cytokine TNF-α with an increase of peritoneal fl uid in women with endometriosis com- pared with women without endometriosis, appears to play a key role in the pathogenesis and progression of endometriosis22. Tumor necrosis factor alpha-blocking agent etanercept can cancel out the in vitro prolifera- tive eff ect of TNF-α on endometriotic cells23. Anti TNF-α therapy has been showed to prevent the de- velopment of induced endometriosis in both rats and baboons, but human data is not available. Inhibition of TNF-α on endometriosis-associated subfertility has not yet been evaluated in preclinical models, and only one human study has been published 24,25.
Etanercept: Etanercept which acts as a TNF inhibitor is a drug that is mainly used in treating autoimmune diseases. Th e eff ects of etanercept on endometriotic implants were evaluated in randomized controlled studies in a rat model. Treated animals showed signifi - cant changes in the volume of lesions, histopathologic scores, and molecular parameters such as serum levels of vascular endothelial growth factor (VEGF), inter- leukin-6 (IL-6), and TNF-α26,27. Barrier et al. suggested that etanercept eff ectively reduced the amount of spon- taneous active endometriosis in the baboons tested in a randomized, controlled, blinded study that included 12 animals received either etanercept or placebo28. Anti Tumor Necrosis Factor Alpha-monoclonal an- tibody (TNF-α-mAb) (c5N): Th e effi cacy of c5N, a specifi c anti-TNF-α-mAb, in the reduction of estab- lished lesions of experimental endometriosis induced
in baboons was also tested in a randomized controlled study29. No impact on the menstrual cycle was found.
In another study, anti TNF-α-mAb treatment signifi - cantly reduced the extent of endometriosis in baboons with induced endometriosis30.
Nuclear Factors kB(NF-kB) Inhibitors
Th e NF-kB peptide family comprises the most im- portant group of transcription factors involved in the infl ammatory and immune responses seen in endome- triosis. Nuclear factor kB is activated by cytokines such as TNF-α and IL-1b. It binds to DNA to determine favoring cell proliferation and inhibiting apoptosis in various cell types including endometrial and endome- triotic cells31-34.
Cell proliferation, motility, adhesion, and invasion abilities were signifi cantly reduced, and apoptosis was increased in vitro32-34. NF-kB suppression was useful in reducing endometriosis establishment and progression in animal models and diminishing endometriosis-asso- ciated symptoms in women.
Statins
Statins are molecules that lower cholesterol synthesis by blocking the conversion of 3-hydroxy-3-methylgl- utaryl-coenzime A (HMG-CoA) into mevalonate, a cholesterol precursor. Th ey also have been demonstrat- ed to inhibit cell proliferation in a number of biologic systems, such as in vitro cultures of eutopic endometrial stromal cells, by mechanisms that have not been clari- fi ed, yet35. Several clinical trials have demonstrated that statins are eff ective for both the primary and second- ary prevention of coronary artery diseases. In addition, statins have been shown to have anti-infl ammatory and anti-angiogenic activity 36.
Lovastatin: Esfandiari et al. suggest that lovastatin, an HMG-CoA reductase inhibitor, can negatively modulate both cell proliferation and angiogenesis in a concentration dependent manner. Lovastatin was also capable of inhibiting stromal cell invasion and angio- genesis in a three dimensional fi brin matrix culture sys- tem37. It is a potent inhibitor of expression of VEGF, which is most probably the mechanism behind the diminished blood-vessel formation. Th ere are reports showing that statins can reduce endothelial cell prolif- eration and migration38.
Other Statins (Simvastatin, Atorvastatin, Endostatin):
Simvastatin added a dose dependent reduction in the
number of viable cells and cell adhesion as well as in- creased apoptosis in culltures of human endometriotic stromal cells (hESCs). Statins have both preventive and therapeutic eff ects on endometriosis39. Atorvastatin signifi cantly inhibited the expression of infl ammatory and angiogenic genes cyclooxygenase-2 (COX-2) and VEGF, and increased the expression of anti-infl amma- tory genes such as peroxisome proliferator-activated receptor g (PPAR-g) in cultures of both eutopic stro- mal and human endometriotic stromal cells40. Yılmaz et al. tested atorvastatin on peritoneal model of endo- metriosis in rodents. However, it has achieved confl ict- ing results in endometriosis-like lesions: in one study there was a statistically signifi cant reduction in the le- sions area, but in another study only intraperitoneal atorvastatin was able to reduce their weight and vol- ume signifi cantly41.
Melatonin
A documented powerful free radical scavenger and broad-spectrum antioxidant molecule, melatonin, which is the major secretory product of the mammali- an pineal gland, has emerged as an important analgesic, antioxidant, and anti-infl ammatory agent. It caused regression and atrophy of endometriotic lesions in rats.
It also, had a more pronounced regression of surgically induced endometriotic foci when compared with let- rozole in a rat model42,43. Th e possible eff ect of mela- tonin on the regulation of endometriosis was tested by interfering with matrix metalloproteinase activity in the mice model. Th e preventive and therapeutic action in endometriosis-like lesions was confirmed, with an increased apoptotic index 44,45.
Mitogen-Activated Protein Kinase (MAPK) Inhibitors P38 MAPK inhibitors (FR167653 and SB203580):
P38 mitogen-activated protein kinase (p38 MAPK) is an intracellular signal-transducing molecule, play- ing an important role in the regulation of a variety of infl ammatory responses, including expression of proinfl ammatory cytokines, leukocyte adhesion and chemotaxis46. Activation of p38 MAPK may be in- volved in the pathogenesis of endometriosis. Specific inhibitors of the p38 MAPK inhibitors SB203580 and FR167653 were tested in a murine model of en- dometriosis. Statistically significant reductions in p38 MAPK phosphorylation and in the weight and size of lesions were observed in the peritoneal fl uid and cells of treated rodents 47,48.
models of deep infi ltrating endometriosis56. Blockage of the mTOR pathway may be considered a novel line of research in the treatment of endometriosis.
Matrix Metalloproteinase (MMPs) Inhibitors
Matrix metalloproteinases are a family of endopepti- dases that play a role in the degredation and turnover of extracellular matrix proteins. Th eir action is regu- lated by specifi c tissue inhibitors called tissue inhibi- tors of metalloproteinases (TIMPs). Derangement of MMP regulation is considered to be a critical factor in the development of pathologic conditions such as en- dometriosis57. Th e mechanism for these actions, as well as many additional regulators of the system, is complex and reviewed elsewhere 44,58.
ONO-4817: Th e MMP inhibitor ONO-4817 was used in the mouse model to determine the develop- ment of experimental adenomyosis58. During the use of MMP inhibitors in the prevention and treatment of endometriosis, care must be taken regarding the side eff ects of excessive TIMP activity on reproduction. In the rat model of endometriosis, recombinant TIMP-1 administration was associated with reproductive ab- normalities such as fewer ovarian follicles and fewer and altered zygotes59.
Apoptotic Agents
Previously published studies comparing patients with endometriosis with normal women showed decreased apoptotic index in ill ones60. Overexpression of anti- apoptotic protein (Bcl-2) was found in stromal cells of proliferative eutopic endometriosis compared to nor- mal endometrium61.
Pro-apoptotic protein (Bax) expression was found to be absent in proliferative endometrium resulting in decreased apoptosis during establishment of endo- metriosis61. Random expressions of Fas were found in eutopic and ectopic endometrial tissues, suggest- ing less involvement of Fas as an apoptotic regula- tor62. Expression of FasL (Fas Ligand) in endometrial stromal cells may induce apoptosis in local immune cells, e.g. macrophage, lymphocyte to promote early endometriosis development63. Reports have also dem- onstrated the involvement of p53, a potent inducer of apoptosis, during malignant transformation of endo- metriosis in human, where p53 staining was found to be negative in benign endometriotic cysts but posi- tive in malignant cysts64.
Immunomodulators
Changes in both cell-mediated and humoral immunity in rhesus monkeys and in women with endometriosis have been observed. Investigators noticed reduced im- mune response to autologous endometrial tissue such as: decreased T cell–mediated cytotoxicity, decreased T cell–dependent B-cell proliferation and decreased lymphocytic infi ltration in response to intradermal in- jection of autologous endometrial antigens49,50. Decreases in natural killer (NK) cell activity, dysfunc- tion of T lymphocytes, infi ltration of macrophages, and aberrant concentrations of immune-related cyto- kines were observed in the peritoneal fl uid of aff ected women51.
IL-12: Peritoneal administration of IL-12 enhanced the cytotoxicity of splenic NK cells and decreased the development of endometriosis-like lesions in rats with induced endometriosis51.
Imiquimod: Imiquimod, an imidazoquinoline, stim- ulates monocytes, macrophages, and dendritic cells to produce cytokines which are important inducers of cell mediated immunity. It is currently used as a topi- cal immune modifi er for the treatment of condylomata acuminata52.
Lefl unomide: Lefl unomide, used mainly in rheuma- toid arthritis, has antiinfl ammatory, antipyretic, and analgesic eff ects. At high doses, its active metabolite A77 1726 suppresses IL-1 and TNF-a production53. Levamisole: Levamisole is currently used as an anti- helminthic drug and as well as an adjuvant in the treat- ment of colorectal adenocarcinomas. Moreover, this molecule can stimulate the formation of antibodies to various antigens, enhance the cellular immune re- sponse provided by T cells, and potentiate monocyte, macrophage, and neutrophil functions54. All these agents were shown to signifi cantly reduce the volume of endometriosis-like lesions, with regression of both glands and stroma, when compared with controls52-54. Ceyhan et al. have shown that treatment with immune modulators or aromatase inhibitors in an experimental model have the potential to regress endometriotic im- plant size55.
Temsirolimus: Temsirolimus is one of the mammalian target of rapamycin (mTOR) inhibitors that are cur- rently available for clinical use and has been approved for the treatment of renal cell carcinoma56. Mammalian target of rapamycin inhibition by temsirolimus alters the phenotype in both in vitro and in vivo mouse
in phase III studies for cancer in China72. In future studies, endostatin may be a new promising hope of treatment of endometriosis.
Angiostatin: Derived from Lewis Lung carcinoma cells, a proteolytic fragment of plasminogen angios- tatin acts directly on activated endothelial cells by inhibition of ATPase activity of endothelial cells73. Angiostatin also inhibits activation of intrinsic and extrinsic apoptosis pathways and VEGF which is elevated in the peritoneal fl uid of endometriosis pa- tients74. Angiostatin gene transfer in a mouse mo- del of endometriosis was studied. A decrease in the number, size, and density of blood vessels and more importantly, endometriosis eradication were estab- lished in all treated mice within 18 days75. Direct injection of angiostatin into macaque preovulatory follicles neither altered ovarian morphology nor had an eff ect on serum progesterone levels76.In ad- dition, in clinical phase I trials angiostatin was well tolerated 77.
Anginex: It has a synthetic angiogenesis inhibitor role in blocking proliferation, adhesion and migra- tion, and in triggerring apoptosis of endothelial cells. Nap et al. showed that anginex reduces the number of established endometriotic lesions in a mouse model of endometriosis78. However, the eff ect of anginex upon reducing endometriosis le- sions was modest and it has not been used in clini- cal trials.
Dopamin Agonists (Cabergoline and Quinagolide):
Dopamine agonists cabergoline and quinagolide inhibit VEGF action and angiogenesis. Th eir ef- fects have not been fully understood. In a human pilot study with 10 hyperprolactinemic patients who had severe endometriosis, it was showed that all noted endometriosis lesions disappeared in two out of nine patients79. Also dopamin agonists are being used in preventing ovarian hyperstimulation syndrome via inhibition of VEGF80.
Other VEGF-inhibitors
TNP-470: A synthetic analogue fungus derived from antibiotic fumagilin, TNP-470 is an eff ective antiangiogenetic agent. Unfortunately, it has inhib- itor eff ects upon maturation of endometrium and corpus luteum and impairs neurons81.
Rapamycin: It is a kind of bacterial macrolide with antifungal and immunosuppressant activ- ity and is used in organ transplanted patients Curcumin: Curcumin, a natural polyphenolic com-
pound used in popular medicine as an anti-infl amma- tory agent, is also reported to be a NF-kB inhibitor and to induce p53-mediated apoptosis65. Curcumin was capable of both preventing and treating induced endo- metriosis in rodents66. With the highest oral curcumin dose in use (150 mg/kg per day), ectopic glandular tis- sue disappeared, and VEGF expression and microves- sel density were proportionately reduced. Th is fi ndings suggest therapeutic potential of curcumin as an anti- endometriotic drug66.
Anti-angiogenetic Agents
It is now well known that angiogenesis and the balance of local pro&anti-angiogenic factors play a key role in the organisation and growth of endometriotic lesions.
Most prominent angiogenic factors in endometriosis are cytokines (IL-1β, IL-6, IL-8), VEGF, TNF-α and hormones (estrogen and progesterone). In endome- triosis, VEGF is known as the most prominent and most studied proangiogenic factor and it is showed that VEGF is the main stimulus for angiogenesis and increased vessel permeability67. Various factors such as estrogen and progesterone, hypoxia, prostaglandin E2, IL-1 and IL-6 enhance VEGF expressions and concen- trations. Donnez et al. discovered higher VEGF in the peritoneal fl uid and lesions of endometriosis patients compared to controls68. It has been thought that inhi- bition of VEGF may be a novel therapeutic approach for the treatment of endometriosis69.
Angiogenesis Inhibitors (VEGF Blocking):
Angiogenesis inhibitors can be divided into two dif- ferent groups; the drugs in fi rst group block proangio- genic cytokines or inhibit the interaction of cytokines with their cellular receptors; and the drugs in second group have a direct inhibitory eff ect on the endothe- lial cells70. We will review these angiogenesis inhibitor drugs as new future treatments.
Endostatin: Endostatin isolated from conditioned media of hemangio-endothelioma cells, is an en- dogenous angiogenesis inhibitor. Becker et al.
showed inhibiting eff ects of endostatin in endo- metriosis lesions of mouse model with both con- tinuous and twice daily subcutaneous doses. It was suggested that endostatin did not have any nega- tive eff ect on reproduction system71. An analogous molecule called endostar has recently been tested
Hyaluronic Acid (HA)
Molecules that prevent implantation of endometrial tissues could be used for treatment. Although there is little known about mechanisms of tissue implantation in endometriosis, HA which has already been used clinically to prevent adhesion formation aft er abdomi- nopelvic surgery could be a new candidate for treat- ment93. Hyaluronic acid reagent suppressed endome- triotic lesion formation in a mouse model94.
Pentoxifylline (PTX)
As a kind of methylxanthine with antiinfl ammatory and antioxidant properties, pentoxifylline, a phos- phodiesterase inhibitor, has been used for many years in the treatment of peripheral vascular diseases.
Th e drug is known to suppress cytokine production, mainly TNF-α in macrophages which induces VEGF production95. In vitro animal models showed that the number, volume and weight of lessions were signifi - cantly reduced aft er PTX injection to endometriotic tissue96. Several human studies have evaluated PTX orally aft er surgery to limit recurrence of signs and symptoms of endometriosis, but no signifi cant im- pact on pregnancy rate and recurrence of symptoms was noted97.
Anti-oxidants
Catalase, superoxide dismutase and glutathione peroxidase/reductase are enzymatic antioxidants.
Vitamin C, A, E and pyruvate and glutathione are also classifed as non-enzymatic antioxidants. Lower antioxidant levels were found in the peritoneal fl uid of infertile women with endometriosis98. Vitamin C (1000mg, 2 tabletsof 500 mg each) and vitamin E (1200 IU, 3 capsules of 400 mg each) therapy given for two months reduced pelvic pain in women with endometriosis99. In an endometriosis established animal model study N-acetyl-L-cysteine (NAC) was administered by gavage with 100 μL of a 10 mg/mL solution in water. At the end of the treatment COX-2 gene expression and MMP-9 activity were decreased.
NAC reduces endometrial mass, by changing cell behavior from proliferation to diff erentiation and decreases tissue infl ammation and cell invasion100. Although the antioxidant vitamins and drugs with antioxidant eff ects have been shown to have some benefi ts in endometriosis, further larger studies are needed because of lack of statistical results and small numbers in current attending studies.
against rejection. Th e inhibitor eff ects of rapamy- cin were showed in a hamster model of induced endometriosis82.
SU5416 and SU6668: In an induced endometriosis study on rodents, it was showed that both VEGF- 2 inhibitors SU5416 and SU6668 had signifi cant blocking eff ects on vessel formation and both re- duced the size of lesions83.
Drugs Effecting Peroxisome Proliferator-activated Receptors (PPAR)
Th iazolidinediones: Th iazolidinediones (TZDs) are insulin sensitizers and clinically used antidia- betic drugs, that activate PPAR. PPAR-γ may be an important factor in endometriosis as a new class of immunomodulators found in endometrial epithelial and stromal cells84. Th ey have also been shown to de- crease aromatase activity in cultured human granu- losa cells85. In a baboon model of established endo- metriosis, PPAR-γ agonist rosiglitazone was given 2 mg/day orally and aft er therapy signifi cant decrease in size of endometriotic lesions was seen86. In report- ed human case series rosiglitazone has also reduced pain87. Although TZDs are clinically used drugs that makes them attractive options for use in clinical trials in endometriosis in the future, they have unwanted side eff ects.
Fenofibrate: Fenofi brates are used in dyslipidemia and atherosclerosis which is an inflammatory disease involving the immune response. A PPAR-α agonist fe- nofi brate showed signifi cant reduction in established endometriosis implants in a rat model of study88.
Metformin
Metformin is an insulin sensitizer agent from the bigu- anid family which is widely used in the treatment of diabetes and polycyctic ovary syndrome. Th e antioxi- dant properties and benefi cal eff ects upon infl amma- tory response has been showed89. In two rat studies, in which abdominal endometriosis was induced, signifi - cant reduction of size and volume of endometriotic le- sions were shown compared to controls90. VEGF and matrix MMPs-9 levels were detected signifi cantly low- er in treated lesion in rats91. In a study where endome- triosis diagnosed using laparoscopy in infertile patients treated with metformin for 3 to 6 months, the levels of VEGF, IL-6 and IL-8 were signifi cantly decreased aft er metformin therapy compared to controls92.
Discussion
Th ere are many new treatment modalities tested in humans and animals. To date, the most extensively used medications in treatment of endometriosis are still COCP and GnRH agonists. Th eir eff ectiveness has been clearly established, but especially side eff ects of GnRH agonists limit their use. Many exciting new classes of agents to treat endometriosis are presently being investigated. Most of these new medications have shown great eff icacy in animal trials. Selective estrogen and progesterone receptor modulators are the most promising agents that are currently availab- le on the markets and that cause less side eff ects than other drugs currently available. New anti-angiogenetic agents, angiogenesis inhibitors and immunomodula- tors may provide a great improvement in treatment of endometriosis.
Th e evidence related with new experimental drugs is limited and larger double-blinded, randomized, placebo-controlled clinical trials of these new agents in humans are needed. On the other hand, the timing of treatment (to start as neo-adjuvant therapy or in post- operative period?) or the safe duration for treatment is unclear. It has been thought that inhibition of VEGF may be a novel therapeutic approach for the treatment of endometriosis.
Gene therapy applications such as viral vectors used for gene transfer have shown to promise in several pre- clinical studies. Anti cancer agents can be an option for treatment of endometriosis as a benign disease in the future. New medical agents for the treatment of endo- metriosis targeting both hormonal and non-hormonal pathways are promising, but their eff icacy and safety are needed to be established in randomized human tri- als before they can be used in routine clinical practice.
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Histone Deacetylase Inhibitors (HDACI)
Because of reduced susceptibility to apoptosis in endo- metriosis, demethylation agents and histone deacety- lase inhibitors (HDACI) might be used in treatment.
Ectopic endometriotic cells survive with the help of down regulation of genes involved in apoptosis101. Romidepsin: Romidepsin, one of the HDACI, re- duced transcriptal activity of VEGF, inhibited cell proliferation and signifi cantly increased apoptosis102. Originally isolated from culture of Cromobacterium violaceum, romidepsin induces p21 gene expression that negatively regulates cell cycle progression and is relevant for inhibition of tumaral cell proliferation.
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Flavanoids
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